The field of this invention is modified polypeptides with improved pharmacokinetics. Specifically, the field of this invention relates to Flt1 receptor polypeptides that have been modified in such a way as to improve their pharmacokinetic profile. The field of this invention also relates to methods of making and using the modified polypeptides including but not limited to using the modified polypeptides to decrease or inhibit plasma leakage and/or vascular permeability in a mammal and to treating various diseases in which plasma leakage and/or vascular permeability occurs, such as inflammatory skin diseases including, for example, psoriasis.
The ability of polypeptide ligands to bind to cells and thereby elicit a phenotypic response such as cell growth, survival, cell product secretion, or differentiation is often mediated through transmembrane receptors on the cells. The extracellular domain of such receptors (i.e. that portion of the receptor that is displayed on the surface of the cell) is generally the most distinctive portion of the molecule, as it provides the protein with its ligand binding characteristic. Binding of a ligand to the extracellular domain generally results in signal transduction which transmits a biological signal to intracellular targets. Often, this signal transduction acts via a catalytic intracellular domain. The particular array of sequence motifs of this catalytic intracellular domain determines its access to potential kinase substrates (Mohammadi, et al., 1990, Mol. Cell. Biol. 11:5068-5078; Fantl, et al., 1992, Cell 69:413-413). Examples of receptors that transduce signals via catalytic intracellular domains include the receptor tyrosine kinases (RTKs) such as the Trk family of receptors which are generally limited to cells of the nervous system, the cytokine family of receptors including the tripartate CNTF receptor complex (Stahl and Yancopoulos, 1994, J. Neurobio. 25:1454-1466) which is also generally limited to the cells of the nervous system, G-protein coupled receptors such as the xcex22-adrenergic receptor found on, for instance, cardiac muscle cells, and the multimeric IgE high affinity receptor Fcxcex5RI which is localized, for the most part, on mast cells and basophils (Sutton and Gould, 1993, Nature 33:421-428).
All receptors identified so far appear to undergo dimerization, multimerization, or some related conformational change following ligand binding (Schlessinger, J., 1988, Trend Biochem. Sci. 13:443-447; Ullrich and Schlessinger, 1990, Cell 61:203-212; Schlessinger and Ullrich, 1992, Neuron 9:383-391) and molecular interactions between dimerizing intracellular domains lead to activation of catalytic function. In some instances, such as platelet-derived growth factor (PDGF), the ligand is a dimer that binds two receptor molecules (Hart, et al., 1988, Science, 240:1529-1531; Heldin, 1989, J. Biol. Chem. 264:8905-8912) while, for example, in the case of epidermal growth factor (EGF), the ligand is a monomer (Weber, et al., 1984, J. Biol. Chem. 259:14631-14636). In the case of the Fcxcex5RI receptor, the ligand, IgE, exists bound to Fcxcex5RI in a monomeric fashion and only becomes activated when antigen binds to the IgE/Fcxcex5RI complex and cross-links adjacent IgE molecules (Sutton and Gould, 1993, Nature 366:421-428).
Often, the tissue distribution of a particular receptor within higher organisms provides insight into the biological function of the receptor. The RTKs for some growth a nd differentiation factors, such as fibroblast growth factor (FGF), are widely expressed and therefore appear to play some general role in tissue growth and maintenance. Members of the Trk RTK family (Glass and Yancopoulos, 1993, Trends in Cell Biol. 3:262-268) of receptors are more generally limited to cells of the nervous system, and the Nerve Growth Factor family consisting of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and neurotrophin-4/5 (NT-4/5), which bind the Trk RTK family receptors, promote the differentiation of diverse groups of neurons in the brain and periphery (Lindsay, R. M, 1993, in Neurotrophic Factors, S. E. Loughlin and J. H. Fallon, eds., pp. 257-284, San Diego, Calif., Academic Press). Fcxcex5RI is localized to a very limited number of types of cells such as mast cells and basophils. Mast cells derive from bone marrow pluripotent hematopoietic stem cell lineage, but complete their maturation in the tissue following migration from the blood stream (See Janeway and Travers, 1996, in Immunobiology, 2d. Edition, M. Robertson and E. Lawrence, eds., pp. 1:3-1:4, Current Biology Ltd., London, UK, Publisher) and are involved in the allergic response.
Many studies have demonstrated that the extracellular domain of a receptor provides the specific ligand binding characteristic. Furthermore, the cellular environment in which a receptor is expressed may influence the biological response exhibited upon binding of a ligand to the receptor. For example, when a neuronal cell expressing a Trk receptor is exposed to a neurotrophin which binds to that receptor, neuronal survival and differentiation results. When the same receptor is expressed by a fibroblast, exposure to the neurotrophin results in proliferation of the fibroblast (Glass, et al., 1991, Cell 66:405-413).
A class of cell-derived dimeric mitogens with selectivity for vascular endothelial cells has been identified and designated vascular endothelial cell growth factor (VEGF). VEGF has been purified from conditioned growth media of rat glioma cells [Conn et al., (1990), Proc. Natl. Acad. Sci. U.S.A., 87. pp 2628-2632]; and conditioned growth media of bovine pituitary follicle stellate cells [Ferrara and Henzel, (1989), Biochem. Biophys. Res. Comm., 161, pp. 851-858; Gozpadorowicz et al., (1989), Proc. Natl. Acad. Sci. U.S.A., 86, pp. 7311-7315] and conditioned growth medium from human U937 cells [Connolly, D. T. et al. (1989), Science, 246, pp. 1309-1312]. VEGF is a dimer with an apparent molecular mass of about 46 kDa with each subunit having an apparent molecular mass of about 23 kDa. VEGF has some structural similarities to platelet derived growth factor (PDGF), which is a mitogen for connective tissue cells but not mitogenic for vascular endothelial cells from large vessels.
The membrane-bound tyrosine kinase receptor, known as Flt, was shown be a VEGF receptor [DeVries, C. et al., (1992), Science, 255, pp.989-991]. The Flt receptor specifically binds VEGF which induces mitogenesis. Another form of the VEGF receptor, designated KDR, is also known to bind VEGF and induce mitogenesis. The partial cDNA sequence and nearly full length protein sequence of KDR is known as well [Terman, B. I. et al., (1991) Oncogene 6, pp. 1677-1683; Terman, B. I. et al., (1992) Biochem. Biophys. Res. Comm. 187, pp. 1579-1586].
Persistent angiogenesis may cause or exacerbate certain diseases such as psoriasis, rheumatoid arthritis, hemangiomas, angiofibromas, diabetic retinopathy and neovascular glaucoma. An inhibitor of VEGF activity would be useful as a treatment for such diseases and other VEGF-induced pathological angiogenesis and vascular permeability conditions, such as tumor vascularization. The present invention relates to a VEGF inhibitor that is based on the VEGF receptor Flt1.
Plasma leakage, a key component of inflammation, occurs in a distinct subset of microvessels. In particular, in most organs plasma leakage occurs specifically in the venules. Unlike arterioles and capillaries, venules become leaky in response to numerous inflammatory mediators including histamine, bradykinin, and serotonin. One characteristic of inflammation is the plasma leakage that results from intercellular gaps that form in the endothelium of venules. Most experimental models of inflammation indicate that these intercellular gaps occur between the endothelial cells of postcapillary and collecting venules (Baluk, P., et al., Am. J. Pathol. 1998 152:1463-76). It has been shown that certain lectins may be used to reveal features of focal sites of plasma leakage, endothelial gaps, and finger-like processes at endothelial cell borders in inflamed venules (Thurston, G., et al., Am. J. Physiol, 1996, 271: H2547-62). In particular, plant lectins have been used to visualize morphological changes at endothelial cell borders in inflamed venules of, for example, the rat trachea. Lectins, such as conconavalin A and ricin, that bind focally to inflamed venules reveal regions of the subendothelial vessel wall exposed by gaps that correspond to sites of plasma leakage (Thurston, G., et al., Am J Physiol, 1996, 271: H2547-62).
The properties of the microvessels are dynamic. Chronic inflammatory diseases, for example, are associated with microvascular remodeling, including angiogenesis and microvessel enlargement. Microvessels can also remodel by acquiring abnormal phenotypic properties. In a murine model of chronic airway inflammation, airway capillaries acquire properties of venules, including widened vessel diameter, increased immunoreactivity for von Willebrand factor, and increased immunoreactivity for P-selectin. In addition, these remodeled vessels leak in response to inflammatory mediators, whereas vessels in the same position in the airways of normal mice do not.
Certain substances have been shown to decrease or inhibit vascular permeability and/or plasma leakage. For example, mystixins are synthetic polypeptides that have been reported to inhibit plasma leakage without blocking endothelial gap formation (Baluk, P., et al., J. Pharmacol. Exp. Ther., 1998, 284: 693-9). Also, the beta 2-adrenergic receptor agonist formoterol reduces microvascular leakage by inhibiting endothelial gap formation (Baluk, P. and McDonald, D. M., Am. J. Physiol., 1994, 266:L461-8).
The angiopoietins and members of the vascular endothelial growth factor (VEGF) family are the only growth factors thought to be largely specific for vascular endothelial cells. Targeted gene inactivation studies in mice have shown that VEGF is necessary for the early stages of vascular development and that Ang-1 is required for later stages of vascular remodeling.
U.S. Pat. No. 6,011,003, issued Jan. 4, 2000, in the name of Metris Therapeutics Limited, discloses an altered, soluble form of FLT polypeptide being capable of binding to VEGF and thereby exerting an inhibitory effect thereon, the polypeptide comprising five or fewer complete immunoglobulin domains.
U.S. Pat. No. 5,712,380, issued Jan. 27, 1998 and assigned to Merck and Co., discloses vascular endothelial cell growth factor (VEGF) inhibitors that are naturally occurring or recombinantly engineered soluble forms with or without a C-terminal transmembrane region of the receptor for VEGF.
Also assigned to Merck and Co. is PCT Publication No. WO 98/13071, published Apr. 2, 1998, which discloses gene therapy methodology for inhibition of primary tumor growth and metastasis by gene transfer of a nucleotide sequence encoding a soluble receptor protein which binds to VEGF. PCT Publication No. WO 97/44453, published Nov. 27, 1997, in the name of Genentech, Inc., discloses novel chimeric VEGF receptor proteins comprising amino acid sequences derived from the vascular endothelial growth factor (VEGF) receptors Flt1 and KDR, including the murine homologue to the human KDR receptor FLK1, wherein said chimeric VEGF receptor proteins bind to VEGF and antagonize the endothelial cell proliferative and angiogenic activity thereof.
PCT Publication No. WO 97/13787, published Apr. 17, 1997, in the name of Toa Gosei Co., LTD., discloses a low molecular weight VEGF inhibitor usable in the treatment of diseases accompanied by neovascularization such as solid tumors. A polypeptide containing the first immunoglobulin-like domain and the second immunoglobulin-like domain in the extracellular region of a VEGF receptor FLT but not containing the sixth immunoglobulin-like domain and the seventh immunoglobulin-like domain thereof shows a VEGF inhibitory activity.
Sharifi, J. et al., 1998, The Quarterly Jour. of Nucl. Med. 42:242-249, disclose that because monoclonal antibodies (MAbs) are basic, positively charged proteins, and mammalian cells are negatively charged, the electrostatic interactions between the two can create higher levels of background binding resulting in low tumor to normal organ ratios. To overcome this effect, the investigators attempted to improve MAb clearance by using various methods such as secondary agents as well as chemical and charge modifications of the MAb itself.
Jensen-Pippo, et al., 1996, Pharmaceutical Research 13:102-107, disclose that pegylation of a therapeutic protein, recombinant human granulocyte colony stimulating factor (PEG-G-CSF), results in an increase in stability and in retention of in vivo bioactivity when administered by the intraduodenal route.
Tsutsumi, et al., 1997, Thromb Haemost. 77:168-73, disclose experiments wherein the in vivo thrombopoietic activity of polyethylene glycol-modified interleukin-6 (MPEG-IL-6), in which 54% of the 14 lysine amino groups of IL-6 were coupled with PEG, was compared to that of native IL-6.
Yang, et al., 1995, Cancer 76:687-94, disclose that conjugation of polyethylene glycol to recombinant human interleukin-2 (IL-2) results in a compound, polyethylene glycol-modified IL-2 (PEG-IL-2) that retains the in vitro and in vivo activity of IL-2, but exhibits a markedly prolonged circulating half-life.
R. Duncan and F. Spreafico, Clin. Pharmacokinet. 27: 290-306, 296 (1994) review efforts to improve the plasma half-life of asparaginase by conjugating polyethylene glycol.
PCT International Publication No. WO 99/03996 published Jan. 28, 1999 in the name of Regeneron Pharmaceuticals, Inc. and The Regents of The University of California describes modified human noggin polypeptides having deletions of regions of basic amino acids. The modified human noggin polypeptides are described as retaining biological activity while having reduced affinity for heparin and superior pharmacokinetics in animal sera as compared to the unmodified human noggin.
The present invention is directed to VEGF antagonists with improved pharmacokinetic properties. A preferred embodiment is an isolated nucleic acid molecule encoding a fusion polypeptide capable of binding a VEGF polypeptide comprising (a) a nucleotide sequence encoding a VEGF receptor component operatively linked to (b) a nucleotide sequence encoding a multimerizing component, wherein the VEGF receptor component is the only VEGF receptor component of the fusion polypeptide and wherein the nucleotide sequence of (a) consists essentially of a nucleotide sequence encoding the amino acid sequence of Ig domain 2 of the extracellular domain of a first VEGF receptor and a nucleotide sequence encoding the amino acid sequence of Ig domain 3 of the extracellular domain of a second VEGF receptor.
In a further embodiment, the isolated nucleic acid of the first VEGF receptor is Flt1.
In a further embodiment, the isolated nucleic acid of the second VEGF receptor is Flk1.
In yet another embodiment, the isolated nucleic acid of the second VEGF receptor is Flt4.
In another preferred embodiment, the nucleotide sequence encoding Ig domain 2 of the extracellular domain of the first VEGF receptor is upstream of the nucleotide sequence encoding Ig domain 3 of the extracellular domain of the second VEGF receptor.
In still another preferred embodiment, the nucleotide sequence encoding Ig domain 2 of the extracellular domain of the first VEGF receptor is downstream of the nucleotide sequence encoding Ig domain 3 of the extracellular domain of the second VEGF receptor.
In a preferred embodiment of the invention, the multimerizing component comprises an immunoglobulin domain.
In another embodiment, the immunoglobulin domain is selected from the group consisting of the Fc domain of IgG, the heavy chain of IgG, and the light chain of IgG.
Preferred embodiments include an isolated nucleic acid molecule comprising a nucleotide sequence encoding a modified Flt1 receptor fusion polypeptide, wherein the coding region of the nucleic acid molecule consists of a nucleotide sequence selected from the group consisting of
(a) the nucleotide sequence set forth in FIGS. 13A-13D (SEQ ID NOS: 13 and 14);
(b) the nucleotide sequence set forth in FIGS. 14A-14C (SEQ ID NOS: 15 and 16);
(c) the nucleotide sequence set forth in FIGS. 15A-15C (SEQ ID NOS: 17 and 18);
(d) the nucleotide sequence set forth in FIGS. 16A-16D (SEQ ID NOS: 19 and 20);
(e) the nucleotide sequence set forth in FIGS. 21A-21C (SEQ ID NOS: 21 and 22);
(f) the nucleotide sequence set forth in FIGS. 22A-22C (SEQ ID NOS: 23 and 24);
(g) the nucleotide sequence set forth in FIGS. 24A-24C (SEQ ID NOS: 25 and 26); and
(h) a nucleotide sequence which, as a result of the degeneracy of the genetic code, differs from the nucleotide sequence of (a), (b), (c ), (d), (e), (f), or (g) and which encodes a fusion polypeptide molecule having the biological activity of the modified Flt1 receptor fusion polypeptide.
In a further embodiment of the invention, a fusion polypeptide is encoded by the isolated nucleic acid molecules described above.
A preferred embodiment is a composition capable of binding a VEGF molecule to form a nonfunctional complex comprising a multimer of the fusion polypeptide.
Also preferred is a composition wherein the multimer is a dimer.
In yet another embodiment, the composition is in a carrier.
Another embodiment is a vector which comprises the nucleic acid molecules described above, including an expression vector comprising a the nucleic acid molecules described wherein the nucleic acid molecule is operatively linked to an expression control sequence.
Other included embodiments are a host-vector system for the production of a fusion polypeptide which comprises the expression vector, in a suitable host cell; the host-vector system wherein the suitable host cell is a bacterial cell, yeast cell, insect cell, or mammalian cell; the host-vector system wherein the suitable host cell is E. Coli; the host-vector system wherein the suitable host cell is a COS cell; the host-vector system wherein the suitable host cell is a CHO cell.
Another embodiment of the invention is a method of producing a fusion polypeptide which comprises growing cells of the host-vector system under conditions permitting production of the fusion polypeptide and recovering the fusion polypeptide so produced.
Additional embodiments include a fusion polypeptide encoded by the nucleic acid sequence set forth in FIG. 10A-10D (SEQ ID NOS: 11 and 12) or FIGS. 24A-24C (SEQ ID NOS: 25 and 26) Which has been modified by acetylation or pegylation wherein the acetylation is accomplished with at least about a 100 fold molar excess of acetylation reagent or wherein acetylation is accomplished with a molar excess of acetylation reagent ranging from at least about a 10 fold molar excess to about a 100 fold molar excess or wherein the pegylation is 10K or 20K PEG.
A preferred embodiment includes a method of decreasing or inhibiting plasma leakage in a mammal comprising administering to the mammal the fusion polypeptide described above, including embodiments wherein the mammal is a human, the fusion polypeptide is acetylated or the fusion polypeptide is pegylated.
A further embodiments is a fusion polypeptide which specifically binds the VEGF receptor ligand VEGF.
A preferred embodiment of the invention is a method of blocking blood vessel growth in a human comprising administering an effective amount of the fusion polypeptide described above.
Also preferred is a method of inhibiting VEGF receptor ligand activity in a mammal comprising administering to the mammal an effective amount of the fusion polypeptide described above.
Preferred embodiments of these methods are wherein the mammal is a human.
Further embodiments of the methods of the invention include attenuation or prevention of tumor growth in a human; attenuation or prevention of edema in a human, especially wherein the edema is brain edema; attenuation or prevention of ascites formation in a human, especially wherein the ascites is ovarian cancer-associated ascites.
Preferred embodiments of the invention include a fusion polypeptide capable of binding a VEGF polypeptide comprising (a) a VEGF receptor component operatively linked to (b) a multimerizing component, wherein the VEGF receptor component is the only VEGF receptor component in the fusion polypeptide and consists essentially of the amino acid sequence of Ig domain 2 of the extracellular domain of a first VEGF receptor and the amino acid sequence of Ig domain 3 of the extracellular domain of a second VEGF receptor.
In a further embodiment of the fusion polypeptide, the first VEGF receptor is Flt1.
In yet a further embodiment of the fusion polypeptide, the second VEGF receptor is Flk1.
Still another embodiment of the fusion polypeptide is one in which the second VEGF receptor is Flt4.
Preferred embodiments include a fusion polypeptide wherein amino acid sequence of Ig domain 2 of the extracellular domain of the first VEGF receptor is upstream of the amino acid sequence of Ig domain 3 of the extracellular. domain of the second VEGF receptor and a fusion polypeptide wherein the amino acid sequence of Ig domain 2 of the extracellular domain of the first VEGF receptor is downstream of the amino acid sequence of Ig domain 3 of the extracellular domain of the second VEGF receptor.
In yet another embodiment, the fusion polypeptide multimerizing component comprises an immunoglobulin domain including an embodiment wherein the immunoglobulin domain is selected from the group consisting of the Fc domain of IgG, the heavy chain of IgG, and the light chain of IgG.
Preferred embodiments include a fusion polypeptide comprising an amino acid sequence of a modified Flt1 receptor, wherein the amino acid sequence selected from the group consisting of (a) the amino acid sequence set forth in FIGS. 13A-13D (SEQ ID NOS: 13 and 14); (b) the amino acid sequence set forth in FIGS. 14A-14C (SEQ ID NOS: 15 and 16); (c) the amino acid sequence set forth in FIGS. 15A-15C (SEQ ID NOS: 17 and 18); (d) the amino acid sequence set forth in FIGS. 16A-16D (SEQ ID NOS: 19 and 20); (e) the amino acid sequence set forth in FIGS. 21A-21C (SEQ ID NOS. 21 and 22); (f) the amino acid sequence set forth in FIGS. 22A-22C (SEQ ID NOS: 23 AND 24); and (g) the amino acid sequence set forth in FIGS. 24A-24C (SEQ ID NOS: 25 AND 26).
Another preferred embodiment is a method of decreasing or inhibiting plasma leakage in a mammal comprising administering to the mammal the fusion polypeptide described above.
An alternative preferred embodiment is a method of inhibiting VEGF receptor ligand activity in a mammal comprising administering to the mammal an effective amount of the fusion polypeptide described above.
One embodiment of the invention is a method of treating psoriasis in a mammal comprising administering a VEGF antagonist to the mammal, and in particular administering VEGFR1R2-Fcxcex94C1(a) to the mammal.
Another preferred embodiment is a method of treating psoriasis in a human comprising administering a VEGF antagonist to the human, and in particular, administering VEGFR1R2-Fcxcex94C1(a) to the human.
Yet another embodiment is a method of reducing the severity of a psoriatic lesion in a mammal comprising administering a VEGF antagonist to the mammal, and in particular, administering VEGFR1R2-Fcxcex94C1(a) to the mammal.
Also preferred is a method of reducing the severity of a psoriatic lesion in a human comprising administering a VEGF antagonist to the human, and in particular, administering VEGFR1R2-Fcxcex94C1(a) to the human.
Still another preferred embodiment is a method of minimizing the extent of hyperproliferation of keratinocytes associated with psoriasis in a human comprising administering a VEGF antagonist to the human and in particular, administering VEGFR1R2-Fcxcex94C1(a) to the human.
Also preferred is a method of reducing the extent of hyperproliferated keratinocytes associated with psoriasis in a human comprising administering a VEGF antagonist to the human, and in particular, administering VEGFR1R2-Fcxcex94C1(a) to the human.
An additional preferred embodiment of the invention is a method of minimizing the extent of epidermal hyperplasia associated with psoriasis in a human comprising administering a VEGF antagonist to the human, and in particular, administering VEGFR1R2-Fcxcex94C1(a) to the human.
One preferred embodiment is a method of reversing epidermal hyperplasia associated with psoriasis in a human comprising administering a VEGF antagonist to the human, and in particular, administering VEGFR1R2-Fcxcex94C1(a) to the human.
Still other preferred embodiments include methods of treating parakeratosis associated with psoriasis in a human comprising administering a VEGF antagonist to the human, in particular administering VEGFR1R2-Fcxcex94C1(a) to the human and treating microabcess associated with psoriasis in a human comprising administering a VEGF antagonist to the human, in particular administering VEGFR1R2-Fcxcex94C1(a) to the human.
Also contemplated is the preferred method of decreasing reteridges associated with psoriasis in a human comprising administering a VEGF antagonist to the human, and in particular, administering VEGFR1R2-Fcxcex94C1(a) to the human.
An additional contemplated embodiment is a method of treating inflammatory skin disease in a human comprising administering to the human VEGFR1R2-Fcxcex94C1(a).
Yet a further embodiment is a method of preventing the infiltration of lymphocytes from the dermis into the epidermis of a human comprising administering VEGFR1R2-Fcxcex94C1(a) to the human.
In preferred embodiments of the invention the administration is topical administration, subcutaneous administration, or perhaps intramuscular, intranasal, intrathecal, intraarterial, intravenous, transvaginal, transdermal, or transanal administration.
Preferred embodiments include the use of a VEGF antagonist to treat psoriasis in a mammal and in particular to treat psoriasis in a human.
A further embodiment is the use of VEGFR1R2-Fcxcex94C1(a) to treat psoriasis in a human.
One embodiment of the invention is a method of treating psoriasis in a mammal comprising administering a VEGF antagonist to the mammal, and in particular administering VEGFR1R2-Fcxcex94C1(a) to the mammal.
Another preferred embodiment is a method of treating psoriasis in a human comprising administering a VEGF antagonist to the human, and in particular, administering VEGFR1R2-Fcxcex94C1(a) to the human.
Yet another embodiment is a method of reducing the severity of a psoriatic lesion in a mammal comprising administering a VEGF antagonist to the mammal, and in particular, administering VEGFR1R2-Fcxcex94C1(a) to the mammal.
Also preferred is a method of reducing the severity of a psoriatic lesion in a human comprising administering a VEGF antagonist to the human, and in particular, administering VEGFR1R2-Fcxcex94C1(a) to the human.
Still another preferred embodiment is a method of minimizing the extent of hyperproliferation of keratinocytes associated with psoriasis in a human comprising administering a VEGF antagonist to the human and in particular, administering VEGFR1R2-Fcxcex94C1(a) to the human.
Also preferred is a method of reducing the extent of hyperproliferated keratinocytes associated with psoriasis in a human comprising administering a VEGF antagonist to the human, and in particular, administering VEGFR1R2-Fcxcex94C1(a) to the human.
An additional preferred embodiment of the invention is a method of minimizing the extent of epidermal hyperplasia associated with psoriasis in a human comprising administering a VEGF antagonist to the human, and in particular, administering VEGFR1R2-Fcxcex94C1(a) to the human.
One preferred embodiment is a method of reversing epidermal hyperplasia associated with psoriasis in a human comprising administering a VEGF antagonist to the human, and in particular, administering VEGFR1R2-Fcxcex94C1(a) to the human.
Still other preferred embodiments include methods of treating parakeratosis associated with psoriasis in a human comprising administering a VEGF antagonist to the human, in particular administering VEGFR1R2-Fcxcex94C1(a) to the human and treating microabcess associated with psoriasis in a human comprising administering a VEGF antagonist to the human, in particular administering VEGFR1R2-Fcxcex94C1(a) to the human.
Also contemplated is the preferred method of decreasing reteridges associated with psoriasis in a human comprising administering a VEGF antagonist to the human, and in particular, administering VEGFR1R2-Fcxcex94C1(a) to the human.
An additional contemplated embodiment is a method of treating a inflammatory skin disease in a human comprising administering to the human VEGFR1R2-Fcxcex94C1(a).
Yet a further embodiment is a method of preventing the infiltration of lymphocytes from the dermis into the epidermis of a human comprising administering VEGFR1R2-Fcxcex94C1(a) to the human.
A further embodiment of the invention is a method of enhancing wound healing in a human comprising administering a VEGF antagonist to the human.
Another preferred embodiment is a method of enhancing wound healing in a human comprising administering VEGFR1R2-Fcxcex94C1(a) to the human.
In preferred embodiments of the invention the administration is topical administration, subcutaneous administration, or perhaps intramuscular, intranasal, intrathecal, intraarterial, intravenous, transvaginal, transdermal, or transanal administration.
Preferred embodiments include the use of a VEGF antagonist to treat psoriasis in a mammal and in particular to treat psoriasis in a human.
A further embodiment is the use of VEGFR1R2-Fcxcex94C1(a) to treat psoriasis in a human.